Compositions and methods for enhanced pharmacological activity of compositions comprising peptide drug substances

ABSTRACT

Pharmaceutical agents, compositions containing the same and methods for their use for enhancing the bioavailability and pharmacological efficacy of therapeutic peptides. The pharmaceutical agents have the formula
 
Carrier-Linker-Peptide
 
Wherein Peptide is a therapeutically active peptide species having the formula aa n  wherein n is the number of amino acid residues in the peptide and n is 2 to 40, Carrier is benzoyl, phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-dimethoxycinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-diethoxy-cinnamoyl, 3,4,5-trimethoxy-cinnamoyl, t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl, N-9-fluorenylmethoxycarbonyl, fumaroyl and derivatives thereof and Linker is a C6 to C16 lipidic chain or a derivative thereof, an 8-amino-3,6-dioxaoctanoic acid or polymeric derivative thereof, pseudo peptide, or peptide mimic. Methods of use of compositions having the formula Carrier-Peptide wherein Carrier and Peptide are as just defined are also disclosed.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-consolidation of application Ser. No.09/844,426 filed Aug. 7, 2000 now abandoned; Ser. No. 10/050,903 filedJan. 16, 2002 now U.S. Pat. No. 6,908,900; and Ser. No. 10/237,254 filedSep. 6, 2002 now abandoned. This application claims benefit under Title35, U.S.C. §119(e), of U.S. application Ser. No. 60/147,749 filed Aug.6, 1999; 60/317,737, filed Sep. 6, 2001; 60/262,337, filed Jan. 17,2001; 60/332,636, filed Nov. 6, 2001; 60/287,872, filed May 1, 2001; and60/287,886, filed May 1, 2001.

FIELD OF THE INVENTION

This invention, in general, relates to compositions and methods thatpermit oral and parenteral administration, and significantly enhance thebioavailability and pharmacological effects of therapeutically activepeptides, pseudo-peptides and peptide mimics, particularly those thatare otherwise poorly orally absorbable or display only minimalbioavailability if administered parenterally.

BACKGROUND OF THE INVENTION

It has been reported in the literature that therapeutically effectivepeptides (aa_(n)) with two or more amino acids (n≧2) are poorly absorbedorally. Even a peptide of as few as two amino acids, or relatedstructures, exhibits very narrow absorption windows and poorbioavailability. As an example, the Physician's Desk Reference (PDR)reports that the angiotensin converting enzyme (ACE) inhibitorEnalaprilat (R₁-Ala-Pro; n=2) is very poorly absorbed orally. Enalapril(R₂-Ala-Pro), which is a pro-drug of Enalaprilat, is better absorbedorally, but the end result demonstrates only a 25% relativebioavailability of the active moiety (Enalaprilat) released from in vivocleavage of the pro-drug. In comparison, Lisinopril (R₃-Lys-Pro) hasrelatively good solubility in water, but only a moderate oralbioavailability (<25%), with a T_(max) (time to maximum serum levels invivo) of more than seven hours. Thus, this class of therapeutic speciesis preferably administered via a non-oral delivery method, such as byinjection. However, even when delivered intravenously, thetherapeutically active species has a relatively short serum half-life.

It is also known that some tri-peptides originating in food products maybe capable of effective oral absorption, but to an unknown extent.However, no active tri- or longer peptide drug substances (n≧3)displaying oral absorption have been identified.

In accordance with the present invention compositions and methodsproviding for the oral absorption of peptide drug substances (aa_(n))and other poorly orally absorbed drugs are disclosed. Furthermore, ithas now been found that, through practice of the methods of the presentinvention, the length of the peptide drug entity (n) can be increased,particularly when the composition is administered parenterally, such asby intravenous (i.v.) administration, with the result of significantlyimproved pharmacological and therapeutic effects for the active drugmoiety. Accordingly, through the practice of the present invention, itis possible to chemically modify a peptide species a pseudo-peptide orpeptide mimic of known therapeutic utility to both permit the oraladministration of the species and to drastically improve itspharmacological properties even when administered through a parenteralroute. The invention also makes it possible to provide a cellular immuneresponse in immunizing against agents such as viruses for whichantibodies have been shown to enhance infectivity and in providing sucha response against both chronic and latent viral infections and againstmalignant cells.

In the present disclosure, the word “peptide” corresponds to anysequence of naturally occurring amino acids, as well as topseudo-peptides and to peptide mimics. By “pseudo-peptide,” is meant achemical modification of one or more of the amino acid residuesconstituting the peptide or of their bonds such as, but not limited to,use of amino acids in their D-configuration, use of N-methyl aminoacids, replacement of one or more peptidic bonds (—CO—NH) by a reducedbond (—CH₂NH) and/or by —NHCO, —CH₂CH₂, —COCH₂, —CHOHCH₂ or —CH2O. By“peptide mimic,” is meant any amino acid sequence in which the —C—backbone has been replaced by an oligourea backbone or an oligocarbamatebackbone. ω-Peptides are also included in this definition.

By “lipopeptides” is meant a combination of natural peptides (notinvolving any modified amino acids or modified bonds) and a lipidmoiety;

By “lipopseudo-peptides” is meant pseudo-peptides coupled with a lipidmoiety.

By “chemically modified amino acid aa_(n)” is meant an amino acidsequence wherein at least one of the amino acid residues in their bondsis modified as set forth above in these definitions.

SUMMARY OF THE INVENTION

The instant invention is directed to pharmaceutical agents having theformulaCarrier-Linker_(x)-Peptide

Wherein X is 0 or 1, Carrier is selected from benzoyl, phenylacetyl,cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl,3,4-dimethoxy-cinnamoyl, 3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl,benzoyloxycarbonyl, pivaloyl, N9-fluorenyl methoxycarbonyl, fumaroyl andderivatives thereof; Peptide is a therapeutically active peptide speciesaa_(n) wherein n is the number of amino acid residues in the peptide andis an integer of 2 to 40 and Linker is selected from C6 to C16 lipidicchains and derivatives thereof, 8-amino-3,6-dioxaoctanoic acid andpolymeric derivatives thereof, pseudopeptides and peptide mimics. Theinvention is further directed to pharmaceutical compositions containingthe afore-identified pharmaceutical agents as active ingredients and tomethods of making and using the same.

In an embodiment of the invention, Carrier or Carrier-Linker is bound toa free NH2 function of the peptide and preferably to the NH2 function ofthe N-terminal amino acid of the peptide;

Carrier is selected from a group consisting of Cinnamoyl,3-OH-Cinnamoyl, 3,4-OH-Cinnamoyl, 3,4-methylenedioxycinnamoyl,3-methoxycinnamoyl, 3-4-dimethoxycinnamoyl, 3,4,5-trimethoxy-cinnamoyland derivatives thereof, and Peptide is a therapeutically active peptidespecies and is in the form aa_(n), where n is the number of amino acidresidues in the peptide and wherein n is an integer from 2 to 40.

In an embodiment, the present invention provides a pharmaceutical agentcomprising a carrier moiety and a therapeutically active peptidespecies, wherein the peptide is in the form aa_(n), where n is thenumber of amino acid residues in the peptide. Preferably, the carriermoiety comprises an aryl or alkyl group of sufficient length or stericbulk to protect the active peptide species from enzymatic degradation invivo. More preferably, the carrier is selected from a group comprisingcinnamoyl, benzoyl, phenylacetyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl,3,4,5-trimethoxy-cinnamoyl, t-butoxycarbonyl, benzyloxycarbonyl,pivaloyl, N-9-fluorenylmethoxycarbonyl, and fumaroyl. Furthermore thecarrier moiety can be chemically linked to a therapeutically activepeptide species of the general formula aa_(n), where n is an integerfrom 2 to 40. In addition, this embodiment of the present inventioncontemplates a therapeutically active peptide species that is poorlyabsorbed orally. Preferably, n is an integer from 3 to 6. Morepreferably, n is 5. More preferably still, the therapeutically activepeptide species comprises Tyr-Gly-Gly-Phe-Met (SEQ ID NO: 1).

In an alternative embodiment, the pharmaceutical agent of the presentinvention further comprises a linker species linking the peptide to thecarrier moiety. Preferably, the linker species is selected from thegroup consisting of a natural peptide, a pseudo-peptide, and a peptidemimic, each member of the group comprising 4 or fewer amino acidresidues. In one aspect of this embodiment of the present invention, thelinker species is directly bound to the carrier. Alternatively, thelinker species is bound to the carrier through a —C₆ or —C₈ acidicmoiety. More preferably, the linker species is Gly-carba-Gly, apseudo-peptide. As used herein Gly-carba-Gly represents a dipseudo-peptide constructed with two glycines, i.e., G ψ (CH₂—CH₂) G. G₉₅ψ (CH₂—CH₂) G₉₆ represents a pseudo-peptide link between two glycines inpositions 95 and 96 of the nef peptide. More preferably still, thelinker species is associated with a —C_(n) chain, where n is an integerfrom 6 to 8. The linker species is bound to a free NH₂ function of thepeptide, preferably to the N-terminal amino acid of the peptide.

Preferably, the therapeutically active peptide species comprisesTyr-Gly-Gly-Phe-Met.

In an alternative embodiment, the pharmaceutical agent of the presentinvention further comprises a linker species linking the peptide to thecarrier moiety wherein the linker species is selected from a groupcomprising a C6 to C16 lipidic chain and derivatives thereof,8-amino-3,6-dioxaoctanoic acid and polymeric derivatives thereof, apseudo-peptide or a peptide mimic of less than 4 residues and anycombination thereof.

In yet another embodiment, the present invention contemplates a methodfor the treatment of a physiological condition through administration ofa therapeutically effective species comprising the steps of chemicallylinking a therapeutic peptide of the general formula aa_(n), where aa isan amino acid, and where n is an integer from 2 to 40, to an alkyl oraryl carrier moiety to form a pro-drug, and administering the pro-drugto a patient exhibiting the physiological condition. Preferably, thetherapeutic peptide used in the practice of the invention is poorlyabsorbed orally, and the carrier moiety is selected from the groupcomprising cinnamoyl, benzoyl, phenylacetyl, 3-OH-cinnamoyl,3,4-OH-cinnamoyl, 3-methoxy-cinnamoyl, 3,4-methylenedioxycinnamoyl,3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl, benzyloxycarbonyl,pivaloyl, N-9-fluorenylmethoxy-carbonyl, and fumaroyl.

Alternatively, this embodiment of the present invention provides amethod wherein the pro-drug is administered orally or parenterally. Inyet another alternative of the present embodiment, the methodcontemplates the use of a therapeutic peptide that is chemically linkedto the carrier moiety through a linker species.

In still another alternative embodiment, the present invention providesa method to enhance the absorption and bioavailability of an activepeptide drug substance of the form aa_(n), in a pharmaceuticalformulation, the method comprising the steps of adding a peptide moietyX_(n), where n=1-3, and where a terminal amino acid is selected from thegroup consisting of Pro, Met and Arg, to one end of the peptide drugsubstance, and adding a protecting moiety to the opposite end of thepeptide drug substance.

Alternatively, the invention of the instant application provides amethod to enhance the absorption and bioavailability of an activepeptide drug substance of the form aa_(n) in a pharmaceuticalformulation, the method comprising the step of formulating the activepeptide drug substance with a terminal amino acid selected from thegroup consisting of Pro, Met and Arg, and with a protective moiety onthe opposite terminus of the peptide substance, wherein the terminalamino acid (Pro, Met or Arg) is not blocked by the protective moiety.

In one embodiment, the present invention provides a pharmaceuticalcomposition for use in the treatment of physiological conditionscomprising a carrier moiety and a therapeutically active peptide speciesas defined above. The carrier comprises an aryl or alkyl group ofsufficient length and/or steric bulk to inhibit rapid enzymaticdegradation of the active drug species in vivo. A preferred carrier isselected from a group comprising cinnamoyl, benzoyl, phenylacetyl,3,4-methylenedioxycinnamoyl, 3,4,5-trimethoxy-cinnamoyl,t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl,N-9-fluorenylmethoxycarbonyl, and fumaroyl. The carrier moiety ischemically linked to a therapeutic peptide of the general formulaaa_(n), where aa is an amino acid, or a chemical or structural variationthereof as defined above, where n is an integer from 2 to 40, andwherein the peptide is poorly absorbed orally. Preferably, in the drugcomposition of the invention, n is an integer from 3 to 6. Morepreferably, n is 5. In a particularly preferred embodiment, the peptideis Tyr-Gly-Gly-Phe-Met (SEQ ID NO: 1).¹ Try=Tyrosine; Gly=Glysine;Phe=Phenylalanine; Met=Methionine.

In another embodiment, the present invention provides a pharmaceuticalcomposition for administration to a patient in need thereof comprisingthe pharmaceutical agent described immediately above, and one or morepharmaceutically acceptable adjuvants. Preferably, the composition isformulated for oral administration. Alternatively, the composition isformulated for parenteral or topical administration. The composition isadvantageously formulated for intravenous administration. Thisembodiment of the present invention also contemplates a composition thatreleases a biologically active form of the pharmaceutical agent into thepatient's system at physiologically effective levels over a period oftime of up to twelve hours. Most preferably, the composition releases abiologically active form of the pharmaceutical agent into the patient'ssystem at physiologically effective levels over a period of time of upto twenty-four hours. In this embodiment of the present invention, thepeptide species is preferably an epitope or an immune sequencecharacteristic of an infectious, viral or cancerous disease.

When delivered orally, the drug composition of the present invention iscapable of delivering a systemic dose of the active drug species to apatient ingesting the pro-drug. The active peptide, normally immediatelydegraded in the gastrointestinal tract to non-therapeutic forms,survives due to the protective effect of the carrier component, andpersists in the patient's system for prolonged periods of time. Overtime, the multi-component system is slowly broken down, probably byenzymatic hydrolysis in the liver or the plasma, releasing thepharmacologically active component. An added benefit of the presentinvention is that the kinetics of such breakdown to release the activecomponent are significantly slower than for the processes associatedwith metabolic breakdown of the unmodified peptide drug species,effectively permitting a sustained, controlled release of the activespecies into the patient's system, thus maintaining pharmacologicallyeffective blood serum levels over an extended period of time.

In another embodiment, the present invention contemplates apharmaceutical composition comprising a similar multi-component entitywhich, when administered through a parenteral route, makes use ofprotective activity towards the enzymatic breakdown provided byassociation of the active drug species with the carrier and/or linkingcomponents, increasing thereby the in vivo half-life of the therapeuticcomponent and improving its pharmacological properties. A preferredtherapeutic moiety for use in this embodiment of the present inventionis an epitope or an immune sequence characteristic of an infectious,viral or cancerous disease. This invention, therefore, provides adelivery method for such immune competent peptides that enhances theirpharmacological efficacy.

As would be recognized by one of skill in the art, one or more of theamino acids of the therapeutically active peptides used in conjunctionwith the present invention may be modified chemically orconformationally without significantly diminishing, and preferablyenhancing, the pharmacological activity of the therapeutic entity. Thesemodified peptides may be used in the practice of the present invention.

Ideally, the composition of the present invention is formulated into apharmaceutical composition with pharmaceutically acceptable adjuvantsknown to those of skill in the art of pharmaceutical formulationchemistry.

Known therapeutically active peptide species that have been demonstratedto be pharmacologically ineffective when delivered through typical oralroutes of administration can be modified through linkage to a carrierspecies to achieve effective bioavailability of the active entity, aswell as therapeutically effective controlled release of the activespecies.

By, utilizing the present invention, it is now possible to treatphysiological conditions through oral administration of therapeuticallyactive peptides that would normally have to be administered throughconsiderably less desirable routes of administra-tion or with lesseffectiveness.

EXAMPLES

Met-Enkephalin (Tyr-Gly-Gly-Phe-Met*) hereinafter (YGGFM) is a naturallyoccurring pentapeptide (n=5) belonging to the endorphin class. It isknown to be involved in the basic mechanisms of analgesia. It produces atransient analgesic effect when administered parenterally, but no effecthas been observed when given orally. Its mechanism of action is believedto involve binding to opioid delta receptors in the brain.Met-Enkephalin is very rapidly degraded in vivo into a tetra-peptidethat is subsequently metabolized. As for the pharmacokinetics ofMet-Enkephalin, the plasma levels of the pro-drug, as well of those ofthe metabolites, are barely measurable, even when administeredparenterally.

Example 1 Analgesic Effects from Administration of CY5M, aCinnamoyl-Met-Enkephalin Pro-Drug of the Present Invention

According to the present invention, a pro-drug, designated CY5M forconvenience of reference, comprising cinnamoyl-Met-Enkephalin(cinnamoyl-YGGFM), having the general forming carrier-aa₅, demonstratedan unexpectedly strong, long-lasting analgesia in a hot plate test withrats both when administered orally, and when administered parenterally.

Methods and Materials

Analgesic activity is classically demonstrated using a hot plate testusing rats as test animals. The time to first licking of the posteriorfoot by the rat is recorded after the rat has been place on a hot platemaintained at an elevated temperature (40° C.). This procedure providesaccurate data on central analgesic activities induced by variouscandidate drugs. Under placebo conditions, the time to first licking ofthe posterior foot of the test animal varies between 30 and 50 seconds.A marked analgesia is demonstrated when this time is more than doubled.In the experiments reported herein, a standard hot plate test was usedto assess analgesia and the time to first licking of the test animal'sposterior foot was used as the triggering event for measurement ofelapsed time as indicative of the pharmacological effect of theadministered drug species.

Seven groups of five male Wistar rats each were randomly assigned to thefollowing treatments: placebo, 1 mg/kg morphine (i.v.), 10 mg/kgmorphine (oral), 10 mg/kg codeine (oral), 10 mg/kg ibuprofen (oral), 2.5mg/kg CY5M (i.v.), and 2.5 mg/kg CY5M (oral). The method waspre-validated with two oral and i.v. administrations of saline placeboand the results were similar to those obtained with placebo in theexperiment reported below.

Results

TABLE 1 Time to first signal activity after oral administration Placebo53.2 30.6 38.4 45.0 46.6 42.0 Morphine 51.8 84.8 81.2 58.8 48.8 42.0Codeine 53.2 51.4 64.6 57.6 56.2 46.4 Ibuprofen 53.2 55.0 70.4 66.0 54.044.2 CY5M 53.6 46.2 78.8 78.2 82.6 98.8

TABLE 2 Time to first signal activity after i.v. administration Time 0 h1 h 2 h 4 h 6 h 24 h Placebo 53.2 30.6 38.4 45.0 46.6 42.0 morphine 51.8118.8 86.6 63.2 45.6 40.0 CY5M 51.0 57.0 114.0 88.2 106.0 86.6

In a preliminary study (data not shown), Met-Enkephalin alone was unableto demonstrate any effect after oral administration at a 5 mg/kg dose,whereas a transient effect of about 15 minutes was observed after i.v.administration.

If the area under the dose response curve is taken as a rough estimateof the average effect, the results indicate that 1 mg/kg morphine i.v.is comparable to 10 mg/kg morphine oral. In comparison, CY5M,administered either orally or by i.v., is at least 8 times moreeffective than morphine using the same route of administration. Offurther interest, the above data also indicate that in no case didmorphine exhibit an analgesic effect lasting longer than six hours,whereas both oral and i.v. administrations of CY5M demonstrated asignificant analgesic effect for a period of time of 24 hours or longer.

These results indicate that using a carrier such as disclosed herein inassociation with a peptide drug species, permits the effective oralabsorption of peptides of at least 5 amino acids in length and allows amuch stronger pharmacological effect, with significantly enhancedpharmacokinetic profiles, by both oral and i.v. routes ofadministration. Analogs of CY5M comprising a linker species in additionto the cinnamoyl carrier species, will demonstrate similar or greatereffects than those provided above.

Example 2 A Series of Carrier-Linker-Peptides Having the FormulaCarrier-(Linker)-Peptide was Tested in their Ability to Induce T CellProliferation in a Skin Immunization Model

Model:

-   -   9 week old mice were immunized by application on bare skin of        100 μg of Nef(₆₆₋₉₇) peptide sequence and modifications thereof        in addition to 5 μg of choleric toxin and 100 μg of        oligodeoxynucleotide containing a CpG moiety (Immunology, 2002        104:1-14). 2 weeks later splenocytes were collected and grown        over 4 days in the presence of 4 different concentrations of        Nef(₆₆₋₉₇) peptide. The proliferation was measured by        incorporating tritiated thymidine.

FormulationsNef=Nef(₆₆₋₉₇): VGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGLLipo=Nef(₆₆₋₉₇)-palmitoyl lysilamideC0=Cinnamoyl-Nef(₆₆₋₉₇)G₉₅ψ(CH₂—CH₂)G₉₆CC5=Cinnamoyl-aminovaleryl-Nef(₆₆₋₉₇)G₉₅ψ(CH₂—CH₂)G₉₆CC8=Cinnamoyl-aminooctanoyl-Nef(₆₆₋₉₇)G₉₅ψ(CH₂—CH₂)G₉₆Pivgal=D-Gal(OPiv)₄-hydroxyvaleryl-aminooctanoyl-Nef(₆₆₋₉₇)G₉₅ψ(CH₂—CH₂)G₉₆

-   -   where G₉₅ψ(CH₂—CH₂) G₉₆ represents the pseudo-peptide chemical        modification of G₉₅-G₉₆ of the Nef(₆₆₋₉₇) sequence.

Results: Proliferation Index

Conc. of Nef peptide: Nef Lipo C0 CC5 CC8 Pivgal 50 10 07 12 20 16 10 513 08 14 21 20 08 0.5 10 06 12 22 22 05 .05 03 03 08 11 10 02

The results clearly show that CC5 and CC8 have the best proliferationindex. The addition to the Cinnamoyl carrier of a covalently boundlinker (Cinnamoyl+fatty acid in C5 or C8) is required to enhance theactivity compared to the baseline. Peptides without the carrier of thepresent invention=peptide+C16 fatty acid (hexadecanoic acid derivative)are not as effective. Derivatives using Pivaloyl carrier did notdemonstrate improved activity. Cinnamoyl alone showed a trend toimproved activity.

The results reported above clearly demonstrate that in certaincircumstances the use of an additional linker may be critical anddepends upon the peptide sequence (Nef(₆₆₋₉₇) compared to YGGFM) and thetherapeutic effect: (pharmacologically active peptide (YGGFM) comparedto immune competent peptide (Nef(₆₆₋₉₇).

The pro-drugs of the present invention are formulated intopharmaceutical compositions that contain an efficacious amount of atleast one lipopseudo-peptide in combination with an inert pharmaceuticalvehicle.

The pharmaceutical compositions contain the derivatives alone or incombination with other medications.

The pharmaceutical compositions of the invention can be administered indifferent forms and by different routes, namely nasal, rectal and oraland by injection.

In the case of administration by the oral route, they may be used in theform of tablets, pills, lozenges, gelatin capsules and even liposomes.These compositions advantageously contain from 0.05 μg to 100 mg oflipo-pseudo peptide, per dosage unit.

The pseudo-peptides of the invention are particularly useful inimproving the immune response against agents such as viruses for whichantibodies have been shown to enhance infectivity, particularly toprovide such a response against Goth chronic and latent viral infectiousand malignant cells.

The present invention also provides a method for enhancing the oralavailability of therapeutic pseudo-peptides of the formula aa_(n), whereaa is a chemically modified amino acid, or a chemical or structuralvariation thereof, where n is an integer of from 2 to 40, and whereinthe pseudo-peptide is poorly absorbed orally, wherein the methodcomprises the step of chemically linking the pseudo-peptide to a carriermoiety selected from the group including cinnamoyl, benzoyl,phenylacetyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl,and 3,4,5-trimethoxycinnamoyl to form a pro-drug. Preferably, thisembodiment of the present invention provides a pro-drug where thepseudo-peptide is chemically linked to the carrier moiety through anon-therapeutic linker species. More preferably, the linker species isan amino acid.

The instant invention also encompasses a method for the treatment of aphysiological condition through the oral administration of atherapeutically effective species comprising the steps of chemicallylinking a therapeutic pseudo-peptide of the formula aa_(n), where aa isa chemically modified amino acid, or a chemical or structural variationthereof, where n is an integer from 2 to 40, and wherein thepseudo-peptide is poorly absorbed orally, to a carrier moiety selectedfrom the group including cinnamoyl, benzoyl, phenylacetyl,3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-methylene-dioxycinnamoyl3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl and 3,4,5-trimethoxycinnamoylto form a pro-drug, and orally administering the pro-drug to a patientexhibiting the physiological condition. Preferably, in the practice ofthe method of the present invention, the peptide is chemically linked tothe carrier moiety through a non-therapeutic linker species. Morepreferably still, the linker species is an amino acid.

Thus, utilizing the present invention, it is possible to treatphysiological conditions through oral administration of therapeuticallyactive pseudo-peptides that would normally have to be administeredthrough considerably less desirable routes of administration, such as byinjection.

In still another embodiment, the invention of the instant applicationprovides for a method for the controlled release administration of atherapeutically effective pseudo-peptide of the formula aa_(n), where aais a chemically modified amino acid, or a chemical or structuralvariation thereof, where n is an integer from 2 to 40, and wherein thepseudo-peptide is poorly absorbed orally, comprising the steps ofchemically linking the peptide to a carrier moiety selected from thegroup comprising cinnamoyl, benzoyl, phenylacetyl, 3-OH-cinnamoyl,3,4-OH-cinnamoyl, 3-methoxy-cinnamoyl, 3,4-dimethoxycinnamoyl,3,4-methylenedioxycinnamoyl and 3,4,5-trimethoxycinnamoyl to form apro-drug, and orally administering the pro-drug to a patient. In apreferred embodiment, the pseudo-peptide is chemically linked to thecarrier moiety through a non-therapeutic linker species, and, morepreferably still, the linker species is an amino acid. Due to thekinetics of the hepatic degradation of the pro-drug of the presentinvention, the therapeutically active peptide species is released to thepatient's system over relatively long periods of time, dosage dependent,to a maximum of nearly twenty-four hours.

1. A pharmaceutical agent having the formulaCarrier-Linker-Peptide wherein Peptide is a peptide having the formulaaa_(n) where n is an integer·40; wherein Carrier comprises an aryl oralkyl group of sufficient length or steric bulk to inhibit rapidenzymatic degradation of the active peptide species and is a memberselected from the group consisting of cinnamoyl, benzoyl, phenylacetyl,3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-methylenedioxycinnamoyl,3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxy-cinnamoyl,t-butoxy-carbonyl, benzyloxycarbonyl, pivaloyl,N-9-fluorenylethoxycarbonyl, fumaroyl, and combinations thereof; andwherein Linker is a member selected from the group consisting of C5 toC16 lipidic chains, 8-amino-3,6-dioxaoctanoic acid, a peptide of lessthan 4 residues, and combinations thereof.
 2. The pharmaceutical agentof claim 1 wherein Linker is a peptide member selected from the groupconsisting of natural peptides, pseudo peptides of less than 4 residuesand peptide mimics of less than 4 residues.
 3. The pharmaceutical agentof claim 1, wherein n is an integer of from 3 to
 6. 4. Thepharmaceutical agent of claim 1, wherein n is
 5. 5. The pharmaceuticalagent of claim 1, wherein Peptide comprises the amino acid sequence ofSEQ ID NO.
 1. 6. The pharmaceutical agent of claim 1 wherein Carrier isa member selected from the group consisting of cinnamoyl,3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3-methoxycinnamoyl,3,4-dimethoxycinnamoyl, and 3,4,5-trimethoxy-cinnamoyl.
 7. Thepharmaceutical agent of claim 1 wherein Carrier is cinnamoyl.
 8. Thepharmaceutical agent of claim 1 wherein Linker is a —C6 or C8 acidicmoiety.
 9. The pharmaceutical agent of claim 1 wherein Linker isG·(CH₂—CH₂)G.
 10. The pharmaceutical agent of claim 1 wherein Peptide isan epitope or an immune sequence characteristic of an infectious, viralor cancerous disease.
 11. A pharmaceutical composition foradministration to a patient in need thereof comprising a pharmaceuticalagent according to claim 1 and one or more pharmaceutically acceptableadjuvants.
 12. The pharmaceutical composition of claim 11 wherein thecomposition is formulated for oral administration.
 13. Thepharmaceutical composition of claim 11 wherein the composition isformulated for parenteral administration.
 14. The pharmaceuticalcomposition of claim 11 wherein the composition is formulated forintravenous administration.
 15. The pharmaceutical composition of claim11 wherein the composition releases a biologically active form of thepharmaceutical agent into the patent's system at physiologicallyeffective levels over a period of time of up to twelve hours.
 16. Thepharmaceutical composition of claim 11 wherein the composition releasesa biologically active form of the pharmaceutical agent into thepatient's system at physiologically effective levels over a period oftime of up to twenty-four hours.
 17. The pharmaceutical compositionaccording to claim 11 wherein Peptide is an epitope or an immunesequence characteristic of an infectious, viral or cancerous disease.18. A pharmaceutical agent having the formula:Carrier-Linker-Peptide wherein Peptide is a peptide having the formulaaa_(n) where n is an integer·40; wherein Carrier comprises an aryl oralkyl group of sufficient length or steric bulk to inhibit rapidenzymatic degradation of the active peptide species and is a chemicalmoiety selected from the group consisting of a cinnamoyl, a benzoyl, aphenylacetyl, a 3-OH-cinnamoyl, a 3,4-OH-cinnamoyl, a3,4-methylenedioxycinnamoyl, a 3-methoxycinnamoyl, a3,4-dimethoxycinnamoyl, a 3,4,5-trimethoxy-cinnamoyl, at-butoxy-carbonyl, a benzyloxycarbonyl, a pivaloyl, aN-9-fluorenylethoxycarbonyl, and a fumaroyl; and wherein Linkercomprises a chemical moiety selected from the group consisting of a C5to C16 lipidic chains, a 8-amino-3,6-dioxaoctanoic acid and polymersthereof, a natural peptide of less than 4 residues, and combinationsthereof.
 19. A pharmaceutical agent having the formulaCarrier-Linker-Peptide wherein Peptide is a peptide having the aminoacid structure of SEQ ID NO. 1; wherein Carrier comprises a cinnamoylmoiety; and wherein Linker is a member selected from the groupconsisting of a —C6 to —C16 lipidic moiety.